In a 9‑year‑old boy with acute lymphoblastic leukemia who is 37 days post‑haploidentical stem‑cell transplantation and now has anemia, thrombocytopenia, schistocytes on peripheral smear, elevated lactate dehydrogenase, mild proteinuria, and a weakly positive direct Coombs test, what is the most likely diagnosis?

Transplant-Associated Thrombotic Microangiopathy (TA-TMA)

The most likely diagnosis is transplant-associated thrombotic microangiopathy (TA-TMA), a life-threatening complication occurring in approximately 10-30% of allogeneic stem cell transplant recipients, typically presenting between days 30-100 post-transplant with the exact constellation of findings described here. 1

Clinical Presentation Matches TA-TMA Criteria

Your patient demonstrates the classic triad of complement-mediated thrombotic microangiopathy occurring in the post-transplant setting:

• Microangiopathic hemolytic anemia: Dropping hemoglobin with schistocytes on peripheral smear and elevated LDH confirm non-immune hemolysis 1, 2
• Thrombocytopenia: Platelet consumption is a cardinal feature of TMA 1
• End-organ involvement: The urine protein:creatinine ratio of 0.2 mg/mg indicates early renal involvement, though marked proteinuria is not required for TA-TMA diagnosis post-transplant 1

The timing at day +37 post-haploidentical transplant is典型 for TA-TMA, which most commonly manifests between 1-3 months after transplantation 1.

Why the Weakly Positive Direct Coombs Test Does Not Exclude TA-TMA

The weakly positive direct Coombs test should not mislead you away from the diagnosis of TA-TMA. 1 While classic atypical hemolytic uremic syndrome (aHUS) presents with a negative direct Coombs test, several important considerations apply here:

• TA-TMA is a complement-mediated process that can occasionally show weak Coombs positivity due to complement deposition (C3d) on red blood cells 1
• The presence of schistocytes as the predominant morphological abnormality strongly favors mechanical hemolysis from TMA rather than immune-mediated hemolysis 3
• In immune hemolytic anemia, you would expect spherocytes rather than schistocytes as the primary red cell abnormality 2

Diagnostic Workup Required Immediately

You must urgently obtain ADAMTS13 activity levels to exclude thrombotic thrombocytopenic purpura (TTP), which requires different management. 1 Key distinguishing tests include:

• ADAMTS13 activity: Severely deficient (<10%) in TTP; normal or mildly reduced in TA-TMA 1
• Complement studies: Consider C3, C4, CH50, and genetic testing for complement pathway abnormalities if available, though treatment should not be delayed for results 1
• Haptoglobin and indirect bilirubin: Should be reduced and elevated respectively, confirming intravascular hemolysis 1, 2
• Reticulocyte count: Should be elevated as a compensatory response, though may be blunted in bone marrow involvement 4

Critical Management Considerations

Immediate consultation with hematology/oncology and nephrology is mandatory, as TA-TMA carries high mortality (50-90%) without prompt intervention. 1 Management principles include:

• Identify and eliminate triggers: Review all medications (calcineurin inhibitors like tacrolimus/cyclosporine are major culprits), assess for GVHD, and evaluate for infections 1
• Consider complement blockade: Eculizumab (anti-C5 antibody) has shown efficacy in TA-TMA, though evidence is still evolving 1
• Plasma exchange is NOT first-line: Unlike TTP, plasma exchange has limited efficacy in TA-TMA and should not delay other interventions 1
• Supportive care: Transfusion support, blood pressure control, and renal protection are essential 1

Alternative Diagnoses to Consider (But Less Likely)

While TA-TMA is most probable, briefly consider:

• TTP: Would require ADAMTS13 <10%, but neurological symptoms are more prominent and it's less common in this specific post-transplant timeframe 1
• Sepsis-related microangiopathy: Schistocytes can occur with severe sepsis, but typically <1% and accompanied by other morphological changes 3
• Drug-induced hemolysis: The weakly positive Coombs could suggest this, but schistocytes would be unusual 2
• Recurrent ALL: Must be excluded with bone marrow evaluation, though the TMA picture is more consistent with TA-TMA 1

Common Pitfalls to Avoid

• Do not wait for "classic" findings: Absence of marked thrombocytopenia or significant anemia should not exclude TMA diagnosis post-transplant 1
• Do not dismiss mild proteinuria: The threshold for renal involvement in TA-TMA is lower than in classic aHUS 1
• Do not assume schistocytes must be >1%: While >1% is more specific, schistocytes as the predominant abnormality at any level warrant concern 1, 3
• Do not delay treatment for genetic testing: Complement pathway mutations may be present, but treatment decisions should be based on clinical presentation 1

The combination of post-transplant timing, microangiopathic hemolytic anemia with schistocytes, thrombocytopenia, elevated LDH, and early renal involvement makes TA-TMA the diagnosis until proven otherwise. 1 Immediate action is required to prevent progression to multi-organ failure.